In the years since the initial discovery that blood from diabetic patients contains increased amounts of a posttranslationally gluco sylated form of hemoglobin (hemoglobin Ale)' an impressive number of studies have clarified and expanded the use of glycohemoglobin levels to assess disease status. Many other structural proteins have been shown to undergo similar changes, including proteins from tissues most commonly affected in diabetes (e.g., lens, aorta, peripheral nerve, basement membrane). Thus, the nonenzymatic glycosylation of hemoglobin emerges as an invaluable model for the pathogenesis of certain chronic diabetes complications. In addition to reviewing a wealth of investigative possibilities in the area of these chronic complications-including eye, kidney, nerve, and vascular disease-Dr. Cohen indicates how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for maintenance of long-term euglycemia. Dr. Cohen is an endocrinologist and diabetes specialist whose research activities have largely focused on the chemistry and metabo lism of the basement membrane in diabetes. This superb monograph on nonenzymatic glycosylation clearly shows the major trends of her past and present research and clinical activities. This book is beautifully written and a pleasure to read. It provides great insight into the mechanisms of the pathogenesis of the oom- vii viii Foreword cations of diabetes and should be of immense value not only to basic and clinical investigators, but also to internists, diabetologists, and endocrinologists in clinical practice."

The flow of information in neuroendocrinology and related disciplines is vigorous, favored by the availability of sensitive and specific biochemical and histochemical techniques that advance our knowledge of CNS neurotransmitter and neuropeptide systems. Volume 8 of Neuroendocrine Perspectives illuminates new findings inthis areawhich add complexity to the traditional view ofthe hypothalamo- pituitary control, and to established concepts ofthe modulation ofbrain function by target hormones. In the first chapter, Ben-Jonathan exhaustively reviews evidence derived from her own work that demonstrates the importance of the posterior lobe as a regulator of prolactin secretion via two opposing influences, i. e. , dopamine released by the tuberohypophyseal dopaminergic system into the short portal vessels and a prolactin-releasing factor which is produced locally, though the identity of its innervating neurons is still unclear. Despite the wealth of information on prolactin and its cell of origin, little is known about the manner in which the hormone exerts its effects on target cells. Frawley and coworkers thoroughlyexamine the direct actions ofprolactin on a broad spectrum ofmammalian tissues, dealing extensivelywith prolactin receptors and the putative second messengers. They also review new evidence, based on their original findings, for an indirect action ofprolactin exerted through the livervia synlactin and liver lactogenic factor, two extracellular modulators ofthe biological functions ofthe hormone. The relationships among the CNS, neuroendocrine and immune systems are bidirectional and constitute an integrated loop.

Obesity is a serious medical problem that affects millions of people, especially in Western societies. Although long considered a complicating factor in a variety of diseases, there is now widespread agreement that obesity itself should be classified and treated as a disease and that it has important conse quences for personal health, quality of life and cost to society. Understanding obesity and the means of treating it have been hampered in the past. There have been misperceptions that obesity is a behavioral disorder and that its treatments provides only cosmetic benefits. Pharmacologic approaches to treatment have suffered from problems of limited efficacy, reduced activity upon chronic use, and serious side effects, including abuse liability, cardiac disease, hypertension, and respiratory complications. Finally, there has been a proliferation of consumer and natural products with unproven benefits. This book attempts to address both the problems associated with obesity and the approaches to treating it. In the first section devoted to pathology, Drs. DIGIROLAMO, HARP, and STEVENS elaborate in Chap. 1 on how obesity and its medical complications develop. As described by Dr. PI-SUNYER in Chap. 2, obesity is a disease seen most often in affluent Western societies and is associated with the aforemen tioned medical problems, as well as Type II diabetes mellitus and gallbladder disease. Drs. CHAGNON, PERUSSE, and BOUCHARD review the human genetics of obesity in Chap. 3, and Drs."

In the middle of the 17th century, the great French philosopher Rene Descartes wrote (L'Homme, J. Le Gras, Paris, 1669) that a suitable stimulation of the brain results in two types of "movements": exterior movements, designed to seek desirable ends and to avoid undesirable or harmful ones and interior movements or "passions" which through the release of "animal spirits" regulate the heart, the liver, and other organs. When it appears appropriate to meet a threat with force, the passion of rage causes the release of strong spirits, whereas when avoidance appears to be the better choice, the passion of fear causes the brain to release weak spirits. We do not know what influence, if any, Descartes had on the thinking of Walter B. Cannon (Bodily Changes in Pain, Hunger, Fear and Rage, Appleton and Co. , New York, 1920), of Hans Selye (The Story of the Adaptation Syndrome, Acta, Inc. , Montreal, 1952), ofG. W. Harris or of R. Guillemin (Hypothalamic-Hypophysial Interrelationships. A Sym posium. c. c. Thomas, Springfield, 1956), but it is interesting to reflect upon the durable value of great ideas which constantly resurface even if modified by other ideas and by new techniques, as if propelled by a preordained intellectual imperative.

For many years now, our understanding of the somatotrophic and reproduc tive axes has evolved essentially independently, both fields of study reaching a highly advanced, although far from complete, level of under standing. Along the way, however, it became apparent that in some circumstances the reproductive and somatotrophic axes may be inter dependent. Inklings to this effect were at times feeble and at other times more convincing. Among those inklings are the clinical recognition by pediatric endocrinologists of the apparent association between isolated GH deficiency and delayed puberty, as well as of the apparent permissive, pUberty-promoting property of GH. Equally important is a body of experi mental studies establishing the ovary of multiple species as a site of GH reception and action. Arguing against an essential role for GH in the reproductive process is the observation that individuals who have GH resistance of the Laron variety are fertile arid that isolated GH deficiency does not constitute an absolute barrier to the attainment of sexual maturation and fertility. The intraovarian insulin-like growth factor (IGF) hypothesis proposes that IGFs may serve as amplifiers of gonadotropin action. Although the dependence of intraovarian IGFs on systemic GH action has never been unequivocally demonstrated, that leap of faith has often been made. The intraovarian IGF hypothesis serves as the rationale for the adjunctive use of GH in the induction of ovulation."

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition.

Lipids and Women's Health is an up-to-date critical review of pertinent scientific and clinical issues connected with lipid disorders in women. Topics discussed include the public health significance of cardiovascular disease in women, lipoprotein and lipid metabolism, effects of estrogens and progestins on lipid metabolism, metabolic changes of menopause, and the paradox of obesity, a curable disease that is rarely cured, as well as those conceptual advances in our understanding of diabetes mellitus that have clarified diagnosis and may have improved treatment. The relationship of diet and lipid intake to the development of breast and uterine cancer; dietary and drug treatment of lipid disorders; effects of exercise, smoking, and stress; and repercussions of lipid disorders on the family are explored. The volume should prove of use to gynecologists, internists, family practitioners, and pediatricians, as well as to all other professionals with a major concern for the health of female patients.

Bilateral Communication Between the Endocrine and Immune Systems, "Volume 7" in the Springer-Verlag "Endocrinology and " "Metabolism" Series, offers the most current information and recent advances in the area of communication and regulation between the Immune and Endocrine Systems. Immune-Endocrine Interactions are reported to play pivotal roles in both activation and down-regulation of immune responses and this volume provides the most up-to-date research and findings on the immune-endocrine relationship. The contributing authors are internationally recognized experts in this area and have written chapters on such diverse topics as Interactions between the Pituitary and Immune Systems, Effects of Estrogens and Androgens on Immune Response, The Role of Sex Steroids in Immune System Regulation, and Neuroendocrine and Thymus Interactions During Development and Aging. This volume is a must for all endocrinologists and endocrinology residents.

This volume in the series Developments in Medical Virology deals with viruses involved in diabetes mellitus, a syndrome with a strong genetic background that causes damage to the regulation of insulin synthesis and function. Viruses were found either to cause or to stimulate diabetes mellitus in man and in animal models. The nature of the role of viruses is described by many of the scientists who participated in the original studies. To complete the picture, chapters were included that deal with the insulin gene, the secondary structure of the proinsulin and insulin receptor polypeptides, pancreatic Langerhans islets, and clinical considerations of the disease. The aim of Developments in Medical Virology is to elucidate processes involving viruses as pathogens of cells and organisms, with special attention to human diseases. A number of volumes will be devoted to viruses affecting specific organs (e.g. brain, liver, etc.), while others will elaborate on the clinical experience in the use of antiviral drugs. The series is published in parallel with Developments in Molecular Virology, designed to present an analysis of molecular mechanisms implicated in virus infection and replicative processes. In addition, the series Developments in Veterinary Virology provides information on viruses causing diseases in animals, with special emphasis on aspects of interest to veterinarians.

Nineteen cutting-edge review articles by leading authorities provide a comprehensive overview of the normal function of the pituitary and of the diagnosis and treatment of pituitary disorders. Topics range from normal hypothalamic-pituitary interactions and the processes that disrupt them to new advances in pituitary imaging and appropriate surgical intervention in various pituitary disorders. Among the diseases discussed are congenital hypopituitarism, deficiency states, strategies for evaluating patients with hyperprolactinemia, Cushing's syndrome, acromegaly, and glycoprotein pituitary tumors.

The traditional concept of a neuroendocrine mechanism for regulation of growth hormone (GH) secretion is based in large part on the work of Roger Guillemin. The work of Dr. Guillemin, who was awarded the 1977 Nobel Prize in Physiology and Medicine, supported the view that quantita tive change in GH secretion was the net result of pituitary stimulation and inhibition by the hypothalamic neurohormones, GH releasing hormone (GHRH), and somatostatin (somatotropin release inhibiting factor; SRIF), respectively. During the 1970s, another endocrine research pioneer, Dr. Cyril Bowers, discovered that structural modification of enkephalin re sulted in a family of peptides with GH releasing properties. These com pounds, simply called GH releasing peptide (GHRP), were originally thought to mimic GHRH. However, upon subsequent investigation they were found to supplement the activity of the natural hormone through a different mechanism. Nearly two decades after their discovery, the differ ences between GHRP and GHRH have been described by many different laboratories throughout the world. The complementary GH secretagogues have different binding sites, second messengers, and effects on gene expres sion. Based on these differences, it has been suggested that expansion of the original two hormone mechanisms for GH regulation to include a third molecule may be appropriate, even though the naturally occurring ana logue of GHRP has not yet been identified. Despite our lack of knowledge concerning the natural product mimicked by GHRP, clinical development of the new family of GH secretagogues for diagnostic and therapeutic purposes has begun in earnest."

A central concept in the evolutionary theory of senescence is the idea that ageing results from life-history trade-offs. In particular, the disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic maintenance (including stress resistance) and in reproduction. Comparative studies among mammalian species confirm that cells from long-lived species appear to have a greater intrinsic capacity to withstand stresses than cells from short-lived species. Childbearing at older ages has become increasingly common in modern societies because of demographic changes, medical progress and personal choice. While the detrimental effects of late reproduction on infant mortality and genetic diseases have been well documented, little is known about the possible postponed detrimental effects of late parenting.

In the words of Disraeli, "To be conscious that you are ignorant of the facts is a great step to knowledge. " For most of us, the conscious awareness of relative ignorance is an uncomfortable aspect of daily life. New data appear in such inexorable profusion that the necessity for continuous retooling has joined death and taxes as an inescapable component of our destinies. Perhaps it is this "consciousness of ignorance" that accounts for the success of the preceding volumes of this new series. The Year in Metabolism and The Year in Endocrinology series were introduced with the avowed intention of "providing an efficient and enjoyable bridge between those who are creating new knowledge at the bedside and the professional consciousness of those for whom such knowledge is ultimately intended. " That objective seems particularly appropriate at a time when the award of the 1977 Nobel Prize in Medicine or Physiology to Guillemin, Schally, and Yalow has served to emphasize the epoch-making advances that have characterized the recent course of endocrinology and me bolism. For the 1977 volume of The Year in Metabolism, the previous formula has been preserved. The same internationally recognized authorities again have contributed commentaries about the progress in their areas of expertise. They have been joined by Drs. Jack W. Coburn, David L. Hartenbower, and Charles R. Kleeman, who have provided a new section on Divalent Ion Metabolism.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition."

The tenth meeting of the International Foundation for Biochemical Endocrinology was held in Geilo, Norway near the end of September, 1982. The subject matter of the conference and the monograph was on "Regulation of Target Cell Respon- siveness." The local organizing committee was Asbjjllrn Aakvaag and Vidar Hansson. The scientific sessions covered a wide range of hormone action and cell response, including: peptide hormones and target cell response, regulation of insulin responsiveness, intracellular modulation of peptide hormone response, gonado- tropins and target cell responses, hypothalamic hormone- effects and regulation, steroid receptors and cellular control, hormones and growth regulation, and hormones and gene regulation. The chairpersons for the sessions were L. Birnbauer -A. Aakvaag, S. Taylor- R. S. Horn, F. Labrie- F. Rommerts, A. R. Means - K. W. McKerns, P. F. Hall - V. Hansson K. Griffiths - K. M. Gautvik, E. J. Peck, Jr. -E. Haug, F. S. French- W. T. Schrader, and E. M. Ritzen- B. Jegou. In addition to the scientific sessions in Geilo we were all delighted to sample some of the cultural and artistic attractions of Oslo, and to travel by train from Oslo via Geilo to Bergen. The scenery and hospitality were magnifi- cant.

The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli nary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of on cology."

The methods of molecular biology, biochemistry, immunocytochem istry, and in-situ hybridization introduce new opportunities for the classification and functional characterization of cell receptors under normal conditions and for a better understanding of pathogenetic mechanisms in human diseases. The cellular localization and trans location of receptor proteins can be identified using morphological methods, and it is apparent that receptors and receptor defects play an important role in pathology, notably in genetic diseases, endocrine disorders, atherosclerosis, infections, and cancer. In this volume in ternational experts give a current review of the morphology and pathological aspects of cell receptors. The complex communication of multicellular organisms is coordi nated by two regulatory systems: neural and humoral. Both systems function via signaling substances (ligands) and signal-recognizing and -transmitting molecules, called receptors. The historical develop ment of the receptor concept is based upon Paul Ehrlich's theory of "receptors in the immune system," Langley's "receptive substances in postssynaptic membranes," and Earl Sutherland's discovery of "sec ond messengers" (cAMP and Ca2])."

Recent years have seen tremendous progress in the field of hormone action and consequent signal transduction. The 40th Colloquium Mosbach was devoted to the discussion of results concerning the molecular process of hormone action, especially the processes following hormone binding to the corresponding receptors. Structural and functional aspects of steroid hormone receptors as well as ion-channel-coupled and enzyme-linked receptors were treated in detail. Particular interest focussed on the latest results concerning transcriptional control, protein phosphorylation, the role of G-Proteins, oncogene proteins, involvement of phospholipases and the regulation of ion channels.

The practice of clinical reproductive medicine has practice in the era of managed care and coordinat gradually moved from its initial 1980-90 hospital ing ancillary offsite medical personnel. base to its present (circa 2001) office site of oper The objective of this text is to assist in this ongo ation. With this transition have been improvements ing endeavor by presenting in a clear, concise man in efficiency of practice often in response to ner many of the topics relevant to contemporary increased pressure to provide the most patient sat office-based infertility practice. The initial half of isfaction. An added challenge of office-based prac this text addresses topics which focus upon general tice has been taking on many of the responsibili concepts of infertility evaluation and practice. The ties of what had been traditionally the hospital's latter half is a practical approach to the execution domain. Some of these new responsibilities have of specific office-based infertility procedures. We included the ordering of operative supplies and hope this book will assist all medical personnel who equipment, the establishment of quality control dedicate their clinical effort in achieving what is programs, construction and maintenance of special most coveted by our patients, the birth of a healthy laboratory spaces, redesigning efficient methods of newborn. DAVID B. SEIFER, M. D. UMDNJ-Robert Wood Johnson Medical School ROBERT L. COLLINS, M. D. The Reproductive Center, Youngstown, Ohio October 2001 vii Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi . . . . . . . . . . . . . . . . . 1 Evaluation of the Female for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bryan D."

Can the art of predictive medicine anticipate the development of diabetes? And if so, what can be done about it? How early is early enough to intervene effectively? With what therapeutic modality? Why? Big babies are not an infrequent occurrence in mothers with normal carbohydrate metabolism for another 10, 20, or even 30 years. The abnor- mality present during pregnancy is now accepted as what is inherited with the diabetic predisposition, or what can be recognized as the diabetic susceptibility. It occurs before hyperglycemia, during the phase of dy- namic resistance to diabetes, during the prediabetic period. Prediabetes means before diabetes, and was applied for the first time by Mara~on in Spain, to signify the stage before hyperglycemia. Foglia in Argentina used the term in 1944 for his pancreatectomized rats. We pub- lished the first paper on humans in 1951 (Camerini-Davalos, R.A., Landabure, P., and Serantes, N., Rev Med Cordoba 39: 187).

Diabetes mellitus represents one of the most frequent and serious clinical syn dromes in contemporary medicine. Since the end of the nineteenth century, the endocrine pancreas has been implicated in the pathogenesis of this disease. Several pathologists of the twentieth century detected various lesions and mor phologic alterations in the pancreatic islets of diabetic patients, but the patho physiologic basis of their findings remained long obscure. The systematic mi croscopic work of WILLY GEPTS clarified the views and related the variety in histopathology to differences in origin, duration and clinical expression of the disease. Over the past two decades, the concept of a multifactorial origin of diabetes has become widely accepted. Various agents and mechanisms have been identified which can lead to a quantitative or qualitative deficit in pancre atic B-cells. The purpose of this book is to bring an update on the many path ways which may induce an absolute or relative insufficiency in insulin release and hence a diabetic state. Rather than bringing a complete account on all re search relevant to the understanding of the pathology of the diabetic pancreas, the authors of the various chapters of this volume have focussed on selected processes which can impair B-cell function, survival or regeneration.

Despite a new title, Contemporary Metabolism, Volume 1 is actually the third volume in a continuing series and succeeds The Year in Metabolism 1975- 1976 and The Year in Metabolism 1977. As in the earlier volumes, the same internationally recognized authorities review the noteworthy recent devel opments in their areas of expertise. In many instances they also address aspects that have not been considered previously. In this volume, Dr. J. Edwin Seegmiller again updates progress in understanding disorders of purine and pyrimidine metabolism. However, particular emphasis is placed on the emerging relationships with immune mechanisms. Dr. Charles S. Lieber is joined by Dr. Enrique Baraona in a continuing review of metabolic actions of ethanol. This chapter examines effects of ethanol on protein metabolism and selected features of lipid metabolism-two areas that were not included in the earlier volumes. Dr. DeWitt S. Goodman's review of disorders oflipid and lipoprotein metabo lism builds on his previous chapters, but much additional attention is directed to a critical analysis of recent advances in epidemiology and lipoprotein structures. In collaboration with Dr. Brian L. G. Morgan, Dr. Myron Winick devotes his entire chapter to a detailed review of the impact of nutrition upon brain development-an overview that has now been rendered possible by the burgeoning recent developments in this area."

Painful Diabetic Neuropathy in Clinical Practice provides a concise, didactic and essential resource for clinicians in the management of neuropathic pain in diabetic patients. This volume opens with overviews of epidemiology, classification and clinical features, including a discussion of the negative effect of painful neuropathic symptoms on quality of life. These are followed by a chapter on diagnosis and staging, which includes approaches to history taking, clinical examination, pain assessment scales, testing and staging. The book concludes with a chapter on the various approaches in the management of neuropathic pain, including the most up-to-date guidelines on the pharmacological treatment of this condition. This concise handbook is an invaluable reference for primary care practitioners and diabetologists who wish to keep up to date with the diagnosis and management of neuropathic pain. Content Level Professional/practitioner